Microtubules compose of α and β-tubulin heterodimers, are major components in eukaryotic cells as they are highly conserved among the eukaryotic proteins (Jordan M A, Wilson L, Microtubules as a target for anticancer drugs, Nat. Rev. Cancer, 2004, (4), 253-265). Microtubules are pleiotropic in their function, particularly in organizing the spatial distribution of organelles in cells and chromosomes during cell division. The dynamic equilibrium between microtubule polymerization and depolymerization is central to most of microtubule mediated functions including cell division. Due to their essential functions in the cell, tubulin dynamics is a promising target for new chemotherapeutic agents. (Dumontet C, Jordan M A, Microtubule-binding agents: a dynamic field of cancer therapeutics, Nat. Rev. Drug. Discov. 2010, (10), 790-803).
Combretastatin (CA-4; S1) and colchicines (S2) are well known compounds that effectively inhibit the tubulin polymerization that leads to antiproliferation of cell. (McGown A. T, Fox B. W, Structural and biochemical comparison of the anti-mitotic agents colchicines, combretastatin A4 and amphethinile, Anti-Cancer Drug Design, 1989, 3, 249; and Ducki S, Forrest R, Hadfield J A, Kendall A, Lawrence N J, McGown A T, Rennison D, Potent antimitotic and cell growth inhibitory properties of substituted chalcones, Bioorg. Med. Chem. Lett. 1998, 8, (9), 1051-1056). Recently it has been reported that a new class of combretastatins such as (Z)-5-(3,5-dimethoxystyryl)-2-methoxyaniline (S4) exhibit potential cell growth inhibition against CA-4 resistant cell lines (BMEC and HT-29) and also explained that in these (Z)-5-(3,5-dimethoxystyryl)-2-methoxyaniline inhibited tubulin polymerization five times stronger than CA-4 by binding at colchicine binding site. (Simoni D, Romagnoli R, Baruchello R, Rondanin R, Grisolia G, Eleopra M, Rizzi M, Tolomeo M, Giannini G, Alloatti D, Castorina M, Marcellini M, Pisano C, Novel A-ring and B-ring modified combretastatin A-4 (CA-4) analogues endowed with interesting cytotoxic activity, J. Med. Chem. 2008, 51, (19), 6211-6215).
More recently a report revealed that a series of (Z)-1-aryl-3-arylamino-2-propen-1-ones (S3) exhibit profound activities against a number of tumor cell lines including multidrug resistant phenotype and the observations made in thus investigation demonstrate that these compounds represent a new class of microtubule-stabilizing agents (Reddy M V, Akula B, Cosenza S C, Lee C M, Mallireddigari M R, Pallela V R, Subbaiah D R, Udofa A, Reddy E P, (Z)-1-aryl-3-arylamino-2-propen-1-ones, highly active stimulators of tubulin polymerization: synthesis, structure-activity relationship (SAR), tubulin polymerization, and cell growth inhibition studies, J Med Chem. 2012, 55, (11), 5174-5187). In continuation of these efforts and our interest in the structural modifications of the combretastatin A4, we describe herein an efficient access to the construction of some new 3,4,5-trimethoxystyrylarylaminopropenones with improved cytotoxicity.
